While the acquisition and use of cocaine continue to have a major impact on public health and safety, advances in the understanding of how cocaine and other drugs of abuse exert their acute and chronic actions on the brain remain elusive. The development of non-invasive functional imaging techniques have provided sensitive and increasingly specific means by which neural processes can be studied with high spatial and temporal resolution. Building upon methods developed and results obtained during the first five years of finding, the experiments proposed in this competing renewal of Project 3 focus on informative rodent models, utilizing chronic cocaine self-administering rats, three lines of knockout mice, as well as drug-naive controls. We propose experiments using functional MRI (fMRI), laser doppler flowmetry, 2-DG metabolic mapping, and in vivo microdialysis methods to study mechanisms of cocaine action. Specific Aim 1 investigates the linkage between dopaminergic activity in brain reward circuits and generation of fMRI signals, and explores the role of serotonergic and GABAergic systems in modulating that activity. Specific Aim 2 utilizes fMRI in mice in which the gene coding for the dopamine transporter, or the D1a receptor, or th4e 5-HT1b receptor has been rendered inoperative. We anticipate that results from these experiments will provide confirmatory evidence to the pharmacological experiments proposed in Specific Aim 1, identifying the role of particular molecular components of dopaminergic and serotonergic signal transduction that contribute to cocaine-induced brain activation. Building upon results from Specific Aim 1, Specific Aim 3 investigates the role of dopaminergic and serotonergic systems in long-term adaptations which occur as a consequence of chronic cocaine exposure using a cocaine self- administration paradigm, the closest animal model of human substance abuse currently available. The hypothesis-driven experiments using state of the art functional imaging techniques that we have proposed in Project 1, in concert with experiments proposed in Project 2, focused on identifying mechanisms coupling psychostimulant administration to cerebral vascular response, are designed to provide a deeper understanding of the mechanism of cocaine action. These experiments in rodents will advance our understanding of acute and chronic effects of cocaine on brain function, facilitating interpretation of data from Project 1, thereby providing a crucial link in understanding the fMRI correlates and neurobiologic consequences of cocaine addiction in humans.